Our broad, long-term objective is to determine the genetic epidemiology of venous thromboembolism (VTE). Segregation analyses show that VTE is highly heritable. The high prevalence of VTE and its known environmental risk factors suggest that multiple genes of varying effects are involved in determining VTE susceptibility. We hypothesize that (1) there are specific discoverable genes and genotypes that greatly increase the risk of VTE, (2) some genotypes may manifest through VTE risk factor exposure, and (3) there are quantitative trait loci (QTL) that pleiotropically affect both plasma hemostasis-related risk factors and VTE. To address these hypotheses, we will use the resources of the eight Thrombophilia Center Pilot sites and the Centers for Disease Control to identify susceptibility genes in high-risk VTE pedigrees. Our specific aims are: Aim 1. To identify and extend high-risk VTE pedigrees, collect demographic and VTE risk factor data and samples for DNA and plasma, and genotype informative individuals within these pedigrees for 500,000 single nucleotide polymorphism-based markers evenly spaced throughout the genome. We will identify at least 75 high-risk VTE pedigrees suitable for linkage studies (at least 3 affected family members and ELOD scores=0.3 or higher);genotyping will be done on ~1200 family members;Aim 2. To map VTE susceptibility genes by genetic linkage analysis. We will use conventional linkage strategies, but we will also implement the latest methods that incorporate environmental covariates in the analysis;Aim 3. Using the high-risk VTE pedigrees and genotypes from Aim 1, (a) to determine the joint action of genes on VTE risk and a number of quantitative hemostasis-related phenotypes;and (b) to identify regions containing genes (e.g., QTL) that influence variation in highly-heritable quantitative phenotypes that genetically correlate with VTE using variance components approach for quantitative traits;and Aim 4. To revise the Mayo Thrombophilia Registry to conform to the Thrombosis/Hemostasis Research Network Registry, and continue data abstraction, prospective outcomes follow-up, and Network Registry data entry for Mayo Thrombophilia Center patients. Implications: Through such efforts, the Network will facilitate the development of a family-based gene-discovery research resource that will be positioned to characterize genetic risk of VTE and to conduct future translational studies, including interventions targeted to high risk groups.